Plasma factor IX (f-IX) levels influence thrombosis risk. Recent discoveries from the Genetics Analysis of Idiopathic Thrombophilia (GAIT) Project demonstrate that: 1) the population variation in thrombosis risk has a high heritability (h2), equal to or > 60%, largely due to unknown genetic factors; 2) a substantial portion of these heritable factors influence thrombosis risk by modulating intermediate hemostasis traits like f-IX; 3) the variation in f-IX levels also involves a substantial genetic component (h2 about 40%) that is entirely unknown; and 4) the variation in thrombosis risk and f-IX levels are strongly correlated genetically (rho[sub g] about 60%), indicating a number of the f-IX quantitative trait loci (QTLs) also influence thrombosis risk. These findings strengthen our proposal because a number of these QTLs are likely to reside in the f-IX locus itself as the expression of this protein is largely regulated at transcriptional and post-transcriptional levels through molecular events involving elements in essential gene regions. Indeed, two f-IX cis-elements, one in the promoter (AE-5') and one in the 3'-UTR (AE-3'), are responsible for the increase in f-IX levels with age. This implies that some of the population variation in f-IX levels may be age-related. Since we found that both age-elements are polymorphic, G-793A in AE-5' and a dinucleotide repeat (DNR) in AE-3', these variations are candidate QTL for f-IX levels and thrombosis risk. Our hypothesis that these variations, along with a f-IX coding region polymorphism (A23387G), modulate f-IX levels and/or catalytic activity, and therefore influence thrombosis risk leads to these Aims: Aim 1: To determine if a single nucleotide (SNP), G-793A, located within an essential f-IX promoter element influences f-IX levels and thrombosis susceptibility. Aim 2: Determine if a polymorphic DNR, which is located in a regulatory element in the 3' -untranslated region (3' -UTR), influences f-IX mRNA stability, plasma f-IX levels and thrombosis risk. Aim 3: Determine if A23387G, a f-IX coding SNP non-conservatively substituting an alanine (Ala) residue for a conserved threonine (thr), influences the rate of f-IX activation, plasma f-IX levels and thrombosis risk. Our long-range goal is to provide more accurate diagnostic approaches, including pre-clinical pedisposition testing, by improving our understanding of the inherited liability to thrombosis, and ultimately to supply the foundation for identifying the interacting factors influencing hemostasis as potential therapeutic targets for more efficacious and safer anticoagulants and antithrombotic agents.